Considerable investigations have been conducted in attempting to grow human calls in other animals to permit the study of such human cells. Background information is provided in several publications and many techniques which are employed in the development of this invention are also described in other publications. To facilitate reference to theme publications, the following legend is provided:
1. Till, J. E. and McCulloch, E. A., Biochem Biophys Acta 605, 431-(1980) PA1 2. Phillips, R. A. (1985), In Ford, R. J. and Maizel, A. L. (eds), New York:Raven Press, 135. PA1 3. Barr, R., Whang-Peng, J. and Perry, S., Science 190, 284-285 1975). PA1 4. Dorshkind, K., Pollock, S. B., Bosma, M. J. and Phillips, R. R., J. Immunol. 134, 3798-3801 (1985). PA1 5. Kenny, J. J., Guelde, G., Hansen, C., and Mond, J. J., J. Immunol. 138, 1363-1371 (1987). PA1 6. Fulop, G., and Phillips R. A., J. Immunol. 136 4438-4443 (1986). PA1 7. Waye, J. S. and Willard, H. P., Nucleic Acids Research 15, 7549-7569 (1987). PA1 8. Erlich, H. C., Gelfand, D. H. and Saiki, R. K., Nature 331, 461-462 (1988). PA1 9. Chervenick, P. A., Boggs, D. R., March, J. C., Cartwright, G. E., and Wintroke, M. M. Amer. J. PA1 10. Matioli, G. Vogel, H. and Nierviseh H., J. Cellular Physiol., 72, 229-234 (1968). PA1 11. Laneuville, P., Chang, W., Kamel-Reid, S., Fauser, A. A. and Dick, J. E., Blood 71, 811-814 (1988). PA1 12. Dick, J. E., Magli, M.-.C., Phillips, R. A. and Bernstein, A., Trends in Genet 2, 165-(1986). PA1 13. Dick, J. E., Magli, M. C., Huezar, D. R., Phillips, R. A. and Bernstein, A., Cell 42, 71-(1985). PA1 14. Kindler, V., Thorens, B., DeKossodo, S., Allet, B., Eliason, J. F., Thatcher, D., Farber, N., and Vassalli, P., Proc. Natl. Acad. Sci. USA 83, 1001-1005 (1986). PA1 15. Donahue, R. E., Wang, E. A., Stone, D. K., Kamen, R., Wong, G. G., Sehgal, P. K., Nathan D. J. and Clark, S. Nature 321, 872-875 (1986). PA1 16. Pauser, A. A. and Messner, H. A., Blood 52, 1243-(1978). PA1 17. D. Belpomme, J. Minowada and G. E. Moore, Cancer 30, 282 (1972). PA1 18. S. Watanabe, Y. Shimosota, M. Kuroki, Y. Sato, T. Nakajima, Cancer Res. 40, 2588 (1980). PA1 19. S. Kamal-Reid and J. E. Dick, Science 242, 1706 (1988). PA1 20. M. Letarts, S. Iturbe and E. J. Quackenbush, Mol. Immunol. 22, 113 (1985); L. J. Picker, J. De Los Toyos, M. J. Telen, B. F. Haynes and E. C. Butcher, J. Immunol. 142, 2046 (1989); L. a. Goldstein et al, Cell 56, 1063 (1989); I. Stamenkovic, M. Amiot, J. M. Pesando and B. Seed, Call 56, 1062 (1989). PA1 21. J. S. Waye and H. F. Willard, Nucleic Acids Res. 15, 7549 (1987). PA1 22. G. A. Carlson, B. A. Taylor , S. T. Marshall and A. H. PA1 23. K. A. Foon and R. F. Todd III, Blood 68, 1 (1986). PA1 24. C. B. Lozzio and B. B. Lozzio, Blood 45, 321 (1975). PA1 25. A. Keating et al, in Normal and Neoplastic Hematopoieses, D. W. Golds, P. M. Marks, Eds. (Alan Liss, N. Y., 1983), pp. 513. PA1 26. G. C. Avanzi et al, British J. Immunol., 69, 359 (1988). PA1 27. T. Papayannopoulou, B. Nakamoto, S. Kurachi, M. Tweeddale, M. Messner, Blood, 72, 1029 (1989). PA1 28. C. Sirard, S. Kamol-REid, J. E. Dock, unpublished results. PA1 29. Z. Estrov, T. Grunberger, I. D. Dube, Y-P. Wang, M. H. Freedman, New Engl. J. Mod., 315, 538 (1986). PA1 30. P. Laneuville, W. Chang, S. Kamel-Reid, A. A. Fauser and J. E. Dick, Blood 71, 811, (1988). PA1 i) irradiating an immunodeficient mouse deficient in T-cells and B-cells with radiation to condition said mouse for transplant; PA1 ii) transplanting into the irradiated mouse the isolated human cells; and PA1 iii) maintaining the mouse to proliferate the human cells in and permit the human cells to spread in the mouse,
Physiol 215, 353-360 (1968).
Greenberg, Immunogenetics 20, 287 (1984).
One area of interest is the cells of the human hematopoietic system. The mature cells within the hematopoietic system have a finite life span and are continuously being replenished by the proliferation and differentiation of lineage specific progenitor cells derived from pluripotent hematopoietic stem cells (Till, J. E. et al, supra). The knowledge of the regulation of this complex cell system, including the identification of various classes of progenitor cells, the protein factors that stimulate their growth, and the molecular events that underlie the abnormalities that occur in diseases such an leukemia, have been derived largely from the development of both in vivo and in vitro assays of the various cells within the stem cell hierarchy. Our understanding of the biology of the human hematopoietic system has suffered relative to the understanding the murine hematopoietic system of the mouse because of the lack of any type of in vivo assay system for pluripotent human stem cells (Phillips, R. A., supra and Ogawa, M. et al. supra).
Previous attempts to grow human bone marrow by direct transplantation into lethally irradiated animals have been unsuccessful (Louwagie, A. C. et al, supra). Implantation into mice of human bone marrow in diffusion chambers has been generally unsuccessful and has not provided evidence for anything more than maintenance of mature human cells for short periods of time (Barr, R. et al, supra).
It is believed that at least in theory, two major barriers may prevent growth of transplanted human bone marrow in irradiated recipient mice; presence of NK cells and absence of human hematopoietic growth factors. Lethally irradiated mice still possess enough immune function to reject the foreign cells. Even immune deficient mice, which lack functional T and B lymphocytes, such as scid and nude have high levels of NK activity which have in the past been understood to mediate a host response against the donor cells (Dorshkind, K. et al, supra and Fostad, O. at al, supra).
Another area of interest in growing human cells to permit in vivo studies is the growth of human leukemic cells. It is very difficult to grow primary human leukemia cells in culture. The difficulties suggest that there are selective processes that may result in alterations of the properties of the cells over time [Belpomme et al, Cancer, 30:282 (1972)]. In spite of the need for in vivo models to develop treatment strategies and an understanding of leukemic transformation and progression, very little progress has been made in the scientific community. Subcutaneous transplantation of lymphoid and mysloid cell lines, lymphomas or primary patient material into nude mice has produced myelosarcomas or localized solid tumors uncharacteristic of the primary leukemia. The growth of human leukemic cell lines in the hematopoietic tissue of nude mice has been described in Watanabe, at al Cancer Res. 38:3494 (1978). The developed cell line in the mouse was a highly aneuploid T-ALL cell line and was maintained in the mouse as an ascites tumor in the mouse. The animals died within two to four weeks. The growth of the human leukemic cells as an ascites or solid subcutaneous tumor in immune-deficient mice does not properly reflect the normal course of the disease as it progresses in humans. The results with human leukemic cells as with human bone marrow cells and many other types of human cells emphasize the need to be able to transplant such cells in a mouse for purposes of in